ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3699_3702dup (p.Leu1235fs) (rs193922343)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491958 SCV000580141 pathogenic Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing The c.3699_3702dupAGAA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of AGAA at nucleotide position 3699, causing a translational frameshift with a predicted alternate stop codon (p.L1235Rfs*4). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000694262 SCV000822698 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1235Argfs*4) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colorectal cancer (PMID: 24689082). ClinVar contains an entry for this variant (Variation ID: 218069). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781589 SCV000919755 likely pathogenic Lynch syndrome 2018-08-29 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3699_3702dupAGAA (p.Leu1235ArgfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Another variant, affecting the same nucleotide positions, and leading to a similar protein level change, c.3699_3702delAGAA (p.Lys1233fsX6) and several other truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3799_3800delAT (p.Met1267fsX7), c.3840_3846delGGAGACT (p.Glu1281fsX44), c.3939_3940dupTC (p.Gln1314fsX14)). The variant was absent in 246004 control chromosomes (gnomAD). The variant, c.3699_3702dupAGAA, has been reported in the literature in an individual affected with colorectal cancer (Hansen 2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287821 SCV001474552 pathogenic none provided 2019-09-19 criteria provided, single submitter clinical testing The MSH6 c.3699_3702dupAGAA; p.Leu1235fs variant (rs193922343), is reported in the literature in an individual affected with colorectal cancer (Hansen 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 218069). This variant causes a frameshift by inserting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, other truncating variants affecting the same nucleotides (c.3699_3702delAGAA) or downstream of the c.3699_3702dupAGAA variant have been reported in families with Lynch syndrome and are considered pathogenic (Goldberg 2008, Nilbert 2009). Based on available information, the c.3699_3702dupAGAA variant is considered to be pathogenic. References: Goldberg Y et al. Mutation spectrum in HNPCC in the Israeli population. Fam Cancer. 2008;7(4):309-17. Hansen MF et al. A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes. Mol Genet Genomic Med. 2014 Mar;2(2):186-200. Nilbert M et al. Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. Fam Cancer. 2009;8(1):75-83.
Mayo Clinic Laboratories, Mayo Clinic RCV000202173 SCV000257274 likely pathogenic not provided no assertion criteria provided research

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